The present invention relates to a novel process for the preparation of clarithromycin represented by formula (I), which has broad antimicrobial activity as a macrolide antibiotic agent, and a novel intermediate that can be used for its synthesis. 
To date, processes for the preparation of the above-mentioned compound of formula (I) are described in Korean Patent Publication Nos. 91-5898, 91-7572, 91-2142, 95-9367, and 96-434, Korean Laid-Open Patent Publication Nos. 90-18132 and 91-7953 as well as several literatures, for example, J. Antibiotics (Vol.46, No.4, 647(1993)), J. Antibiotics (Vol.46, No.7, 1163(1993), J. Antibiotics (Vol.37, No.2, 187(1984)), Heterocycles (Vol.36, No.2, 243(1993)), and J. Antibiotics (Vol.43, No. 3, 286(1990)). These processes may be summarized in the following three ways:
 less than Process 1 greater than 
This process comprises protecting 3xe2x80x2-N,N-dimethylamino group and 2xe2x80x2-OH group of erythromycin 9-oxime derivative, wherein an OH group is protected, with a carbobenzyloxy(Cbz) group and then methylating the hydroxyl group at the 6 position of said compound (see Korean Patent Publication Nos. 91-5898 and 91-7572). However, this process has the disadvantages that an excess Cbz-Cl that is relatively expensive should be used, and even though the deprotection is carried out by the hydrogen reaction, this reaction is not completed on account of the catalytic poison. Further, since the methyl group of 3xe2x80x2-N,N-dimetylamino group of said compound has to be regenerated by methylation in the final step of the process, it has the additional disadvantages that it is difficult to perform the process, and the process is lengthy. This process may be represented by the following scheme: 
 less than Process 2 greater than 
This process comprises protecting 3xe2x80x2-N,N-dimethylamino group of erythromycin 9-oxime derivative, wherein an OH group is protected, with a quaternary salt of an identical group (for example, benzyl group)(see Korean Patent Publication No.91-2142). Since the deprotection in this process is also carried out by using hydrogen as in process 1, it has the disadvantage that the reaction is not completed on account of the catalytic poison as in Process 1. This process may be represented by the following scheme: 
 less than Process 3 greater than 
This process comprises protecting an oxime of erythromycin 9-oxime derivative with a benzyl or ketal derivative, and protecting 2xe2x80x2-OH group and 4xe2x80x2-OH group of said compound with substituted silyl groups, and then methylating a 6-OH group of said compound, and finally deprotecting a protecting group of 9-oxime and trimethylsilyl group of said 2xe2x80x2-O- and 4xe2x80x3-O-groups of said compound simultaneously in a relatively short step to obtain the desired compound.(see Korean Patent Publication Nos. 95-9367 and 96-434). In this case, the 9-oxime derivative used in the trimethylsilylation of 2xe2x80x2-OH and 4xe2x80x2-OH groups should be used in the salt free form. This process is represented by the following scheme: 
In accordance with the above reaction scheme, the yield of clarithromycin synthesized from an erythromycin A is about 45 to 50%. In the cases where a benzyl derivative is used to protect an oxime for the above reaction schemes, it is difficult to perform such lengthy reactions since the deprotection is carried out by using hydrogen. Another shortcoming is that the ketal derivative, which is used to protect an oxime, has to be used excessively (with about 2 to 3 equivalents) and the total reaction time is rather lengthy. Despite of such shortcoming, the ketal derivative and trimethylsilyl groups can be simultaneously eliminated by an acid treatment.
In efforts to eliminate saprophytic matters that are produced during the 3 synthetic processes mentioned above, a purification step involving precipitation of the synthesized clarithromycin is included in the above processes. However, in most cases, there is about 10 to 20% drop in the yield. In addition, an elimination of saprophytic matters is very difficult if the saprophytic matters having similar characteristics to those of clarithromycin are present.
Accordingly, the inventors have extensively studied a new process for preparing the desired compound in order to solve the above problems of conventional methods and to increase the yield. As a result, it has been found that 1, 3-benzodithiol-2-ylium tetrafluoroborate(BDTF)(Syn. Commun., 471(1976)) represented by the following formula, which is simply synthesized from anthranilic acid, can be used as a protecting group for oxime. The present invention was made possible by means of developing a new and simple process for preparing a high yield of clarithromycin. 
It is an object of this invention to provide an erythromycin A 9-O-BDT oxime intermediate represented by the following formula (III), which is useful for the synthesis of clarithromycin prepared by reacting an erythromycin A 9-oxime or hydrochloride thereof with BDTF. 
Wherein, Y1 and Y2 represent hydrogen atoms or trimethylsilyl groups.
Additionally, the present invention provides the compound of the formula (III) (Y1 and Y2 are trimethylsilyl groups) crystallized in the mixed solvent comprising 5 to 10 parts by weight of acetone and 1 to 5 parts by weight of water. The ratio of the compound of said formula (III) and acetone is 2:1.
Furthermore, it is another object of this present invention to provide a process for preparation of clarithromycin, which comprises the steps of:
1) reacting an erythromycin A 9-oxime of the following formula (II) or hydrochloride thereof with 1.0 to 1.2 equivalents of 1, 3-benzodithiol-2-ylium tetrafluoroborate (BDTF) in an aprotic non polar organic solvent in the presence of 1.0 to 2.0 equivalents of pyridine to form an erythromycin A 9-O-BDT oxime derivative of the following formula (III)xe2x80x2 having an oxime group which is protected with a benzodithiol(BDT) group, as shown in the following scheme; 
2) reacting a compound of formula (III)xe2x80x2 synthesized in the above step 1) with 3.0 to 5.0 equivalents of hexamethyldisilazane(HMDS) in the presence of salts such as ammonium chloride, pyridine hydrochloride, pyridine p-toluene sulfonate to form 2xe2x80x2-O,4xe2x80x3-O-bistrimethylsilyl-erythromycin A 9-O-BDT oxime derivative of formula (V), as shown in the following scheme; 
3) methylating a 6-OH group of the compound of formula (V) synthesized in the above step 2) with 2.0 to 3.0 equivalents of methyl iodide in an aprotic polar solvent in the presence of a strong base to form 2xe2x80x2-O-,4xe2x80x3-O-bistrimethylsilyl-6-O methyl-erythromycin A 9-O-BDT oxime derivative of the following formula (VII) as shown in the following scheme; 
4) deprotecting a compound of formula (VII) synthesized in the above step 3) to form the following formula (I).BSDA compound as shown in the following scheme and; 
5) simply stirring the formula (I).BSDA compound synthesized from the step 4) in water or mixed solvent of water and water-miscible organic solvent in the presence of an inorganic salt or a base, and then filtering it to form the following scheme representing the formula (I): 
According to the present invention, step 1 is carried out by reacting an equivalent of erythromycin A 9-oxime representing the above formula (II) or hydrochloride thereof with 1 to 2 equivalents of BDTF in an aprotic nonpolar organic solvent in the presence of 1 to 2 equivalents of pyridine to form erythromycin A-9-O-BDT oxime derivative of the above formula (III)xe2x80x2 having an oxime group, which is protected with 1, 3-benzodithiol-2-ylium (BDT) group.
Step 2 is carried out by reacting the resulting compound of the formula (III)xe2x80x2 in the above step 1 with 3 to 5 equivalents of hexamethyldisilazane (HMDS) in the presence of salts such as ammonium chloride, pyridine hydrochloride, pyridine p-toluene sulfonate to form 2xe2x80x2-O-, 4xe2x80x3-O-bistrimethylsilyl erythromycin A 9-O-BDT oxime derivative of the above formula (V).
According to the present invention, a methylation of the compound of the above formula (V) at 6-OH group is carried out in an aprotic polar solvent (such as DMSO or DMF), or a mixture ratio of 1:1 of said aprotic polar solvent and THF(tetrahydrofuran), or a mixture ratio of 2:2:0.3 of said aprotic solvent, THF and a non-polar organic solvent (such as isopropylether or t-butylethylether) in an amount of 5 to 10 times that of the compound of the above formula (V) to synthesize the formula (VII). The reaction, which takes about 30 minutes to 2 hours, has to be carried out in the presence of 0 to 2.5 equivalents of Et3N, 1 to 3 equivalents of a strong base such as NaH, alkoxide, KOH and NaOH, and 2 to 3 equivalents of a methylating agent namely methyl iodide at a temperature of xe2x88x925 to 5xc2x0 C.
The compound of the above formula (VII) of the present invention is then deprotected by using 1 to 3 equivalents of formic acid (HCO2H) and 4 to 8 equivalents of NaHSO3, Na2SO3, Na2S2O4, or Na2S2O5, and ethanol and water ratio of 1:1 in 5 to 10 parts by weight of the mixed solvent of 1:1 of ethanol and water by refluxing with heat for 4 hours. As a result, 1, 3-benzodithiole-2-sulfonic acid (BDSA) of clarithromycin representing the above formula (I) is synthesized.
BDSA, which is synthesized by reacting a protective group, BDT, with a deoximizing agent such as NaHSO3, Na2SO3, Na2S2O4, or Na2S2O5 in the presence of HCOOH, forms into its salt form, represented as the above formula (I).BDSA when joined with a 3xe2x80x2-N,N-dimethylamino group. After the reaction is completed and the temperature is lowered to room temperature, the desired compound, which is crystallized in the reaction solvent, is then purified. As a result, the separation of the desired compound from the other by-products becomes very feasible. In this case, since the reaction between a BDT group and a deoximizing agent occurs first in the order of deprotection, oxime is synthesized without having any protection. Clarithromycin is synthesized as a result of a deoximization and an elimination of trimethlysilyl group in the final step.
According to a process of the present invention, the above formula (I).BDSA is reacted with an inorganic salt such as K2CO3, Na2CO3, or KOH to remove BDSA in a neutralizing reaction and finally a pure crystal form of clarithromycin representing the above formula (I) is obtained.
It is yet another object of this invention to provide another process for the preparation of clarithromycin of formula (I) by adding hexamethyldisilazane (HMDS) to erythromycin A 9-oxime representing the formula (II) or hydrochloride thereof to form 2xe2x80x2-O,4xe2x80x3-O-bistrimethylsilyl-erythromycin A 9-oxime derivative of formula (IV) in place of the above step 1), and reacting 2xe2x80x2-O-,4xe2x80x3-O-bistrimethylsilyl-erythromycin A 9-oxime derivative of formula (IV) in an aprotic organic solvent such as MC in the presence of pyridine with 1 to 2 equivalents of BDTF to form a quantitative yield of 2xe2x80x2-O-,4xe2x80x3-O-bistrimethylsiliyl-erythromycine A 9-O-BDT oxime derivative of formula (V) in place of the above step 2), as shown in the following scheme; 
Once the compound of the above formula (V) is mixed and dissolved in a mixed solvent of 1 to 5 parts by weight of water and 5 to 10 parts by weight of acetone (preferably in the mixture ratio of 3:10) to form a crystalline solvate comprising the compound of the above formula (V) and acetone in 2:1 ratio.
The following are examples to illustrate the present invention in further detail but they do not limit the scope of the invention in anyway.